It has been found that certain pharmaceuticals are absorbed to a degree through the skin. This is referred to as transdermal pharmaceutical absorption. One means of effecting transdermal absorption has been to distribute the pharmaceutical within a polymeric disc or a container of a gel, which is brought into contact with an area of the skin of the subject to be treated with the pharmaceutical. Also, ointments or lotions containing a desired pharmaceutical have been applied to an area of the skin of the subject to be treated. Problems encountered in such treatment include inadequate control over the rate and duration of transdermal absorption or the rate can be too slow in the case of certain dosage forms, especially from pharmaceutical-containing discs or pharmaceutical-containing gel container dosage units or pads. It has been found that the transdermal absorption rates of certain pharmaceuticals can be increased by use of absorption promoting compounds (also referred to as skin permeation enhancers) with the pharmaceutical to be absorbed when compounding the polymeric disc or the pharmaceutical-containing gel.
It is desired to improve the dosage unit forms or devices by which pharmaceuticals are transdermally absorbed, especially in view of the importance of administration of pharmaceuticals by this means. Desired transdermal absorption of pharmaceuticals would provide an avoidance of gastrointestinal incompatibility with the pharmaceuticals and unwanted destruction of the pharmaceutical by metabolism in the gastrointestinal tract and by a "first pass" hepatic metabolism. The transdermal absorption minimizes inter- and intra-patient variations regarding such incompatibilities and metabolisms. By transdermal absorption, it is deemed possible to provide more constant pharmaceutical concentration in the body and to realize a greater pharmaceutical efficiency. It is possible, by proper transdermal absorption, to reduce the frequency of effective dosing. Transdermal administration provides most of the advantages of intravenous dosing without the necessity of hospitalization and the accompanying discomfort and inconvenience.
With regard to specific pharmaceuticals to which this invention is directed, the estrogenic steroid estradiol is an illustration of a pharmaceutical in which great loss of orally administered estrogen occurs by first-pass through the liver, it being almost completely metabolized. Therefore, oral administration of estradiol is not a satisfactory means of replacing normal levels of estradiol. It has been found that by transdermal administration, estradiol can be provided, in only a fraction of the amount required in oral dosing, to achieve adequate levels of estradiol, which the body for one or more reasons is not naturally producing to provide adequate levels in women to prevent body conditions and symptoms caused by such inadequate levels. Also, by transdermal administration of estradiol, for example, the unwanted estradiol metabolites produced by first-pass hepatic metabolism are greatly reduced. An additional advantage of transdermal administration is the attainment of more constant levels of estradiol and other estrogenic steroids.
The need for estradiol replacement therapy is caused by menopause (the cessation of ovarian function), oophorectomy (loss of one or both ovaries by surgery) or by pituitary failure. Replacement estrogenic therapy is an important need. Besides the need to alleviate the menopausal symptoms caused by estrogenic steroid deficiency, there are additional contributions of such replacement estrogenic therapy associated with osteoporosis (loss of bone mass) and atherosclerosis. There is clearly a need for improvements in means and methods for estrogenic steroid therapy. Even though it has been found that estradiol itself or estradiol in the form of certain derivatives such as mono- or diesters (e.g., acetate esters) can be absorbed transdermally, it is desired that improved transdermal estradiol and other estrogenic steroid absorption dosage unit forms and processes of transdermal administration be developed. A number of advantages would result.